To stem the growing national problem of osteoporotic fractures, there is an urgent need to better identify high- risk individuals for treatment. During the current funding cycle, we have applied innovative techniques to assess biomechanically relevant bone structure using 3-dimensional (3-D) quantitative computed tomography (QCT) and contributed to revising the new US version of the World Health Organization's fracture prediction model, FRAX(R) (US-FRAX). In this renewal application, we propose to use novel approaches in imaging, biomechanical image analysis, biomarkers, and functional assessments to further enhance our understanding of the structural and functional deficits that contribute to skeletal fragility and fracture risk. Our four Specific Aims address critical diagnostic and therapeutic issues at key stages of life: (1) To characterize optimal skeletal development by determining the basis for adolescent forearm fractures in a population-based case- control study by using high resolution peripheral QCT (HRpQCT) ("non-invasive bone biopsy") to test whether those sustaining such fractures have specific deficits in bone structure and strength (AIM 1a) and defining the role of lifestyle and hormonal factors in modulating the skeletal parameters that discriminate cases from controls and determine peak bone strength (AIM 1b);(2) To better identify candidates for intervention by characterizing the early postmenopausal women who will experience rapid bone loss by using HRpQCT to test that early changes in bone microstructure predict which women with osteopenia will experience rapid bone loss at the hip and spine over 3 yrs (AIM 2a);evaluating whether this prediction can be improved by novel biomarkers (AIM 2b);and applying new dual-energy QCT to quantify confounding by perimenopausal changes in marrow fat (AIM 2c);(3) To advance the epidemiology of bone structure and strength using our highly detailed QCT and HRpQCT scans to exploit ongoing advances in biomechanical image analysis to better define changes in bone fragility and fracture risk at the hip, spine and wrist in women and men over life (AIM 3a);and determining risk factors for the critical structural elements primarily responsible for age-related reductions in bone strength (AIM 3b);and (4) To address key unresolved issues involved in translating FRAX(R) to clinical practice by validating the newly revised US-FRAX for long-term fracture outcomes in a population- based cohort of women and men and determining whether additional risk factors (e.g., bone turnover, fall history) independently contribute to fracture prediction (AIM 4a);and examining the relation between fall risk, evaluated using novel 3-D gait analysis techniques, and US-FRAX scores to determine whether fall risk, independent of age, should be individually characterized for improved fracture risk assessment (AIM 4b). We believe the proposed work will have an important impact by providing deeper insight into the structural and functional basis for age-related fractures, and it addresses significant translational questions arising from the need for better data upon which to base individualized treatment decisions. PUBLIC HEALTH RELEVANCE: Osteoporosis is an enormous public health problem, but the potential expense and side-effects associated with pharmacological treatment are such that it is critical to better identify those at greatest risk for fracture. We focus on better defining the key structural and functional deficits that determine bone strength and fracture risk and seek to refine our knowledge of the risk factors that influence these parameters. A better understanding of the structural basis and risk factors for fractures should help identify the individuals who might benefit most from interventions.